Regulation of Lipid Metabolism and Cell Cycle Progression By PU.1 in Myeloid Progenitor Cells
Bibliographic record
Abstract
Abstract PU.1 is a transcription factor essential for myeloid development. High PU.1 expression leads to myeloid differentiation and cell cycle arrest while low expression leads to increased proliferation and self-renewal. Reduced PU.1 can lead to the development of acute myeloid leukemia. PU.1 induces microRNAs targeting genes involved in cell cycle and lipid metabolism. Included in these genes are E2f1 and Acly that are associated with lipogenesis. E2F1 is directly involved in cell cycle activation and lipid metabolism. Acly encodes ATP citrate lyase (ACL) that is responsible for the production of acetyl-CoA from mitochondrial citrate. Acetyl-CoA is the first precursor molecule for lipid biosynthesis, and lipogenesis is essential for proliferation. Therefore, we hypothesized that PU.1 activates genes encoding microRNAs to downregulate E2F1 and ACL, leading to cell cycle arrest. To test this hypothesis, we utilized a PU.1 inducible cell line system that is derived from myeloid progenitor cells in the liver of fetal BN mice (Spi1BN/BN) that express PU.1 at 20% of normal levels (iBN cells). Following doxycycline administration, iBN cells can be induced to express high levels of PU.1, causing cell cycle arrest and differentiation of these myeloid progenitor cells into a macrophage like phenotype. MicroRNA (miR)-223 and miR-141 were identified as PU.1 inducible miRs that target E2f1 and Acly, respectively. Supplementation with acetyl-CoA or acetate significantly rescued cell cycle inhibition caused by PU.1 induction. Inhibition of ACL activity by the chemical inhibitor BMS303141 (BMS) was sufficient to reduce cell cycle progression in cultured iBN cells. Supplementation with acetyl-CoA or acetate significantly rescued cell cycle progression in iBN cells inhibited with BMS. To determine if ACL levels play a role during normal macrophage differentiation, we investigated mRNA transcript levels of Acly over the course of myeloid progenitor differentiation promoted by M-CSF or GM-CSF. We found that Acly mRNA transcript levels inversely correlated with Adgre1 (encoding F4/80) or Spi1 (encoding PU.1) during macrophage differentiation. We conclude that during myeloid differentiation, PU.1 regulates the expression of genes involved in lipid metabolism through miRs, and influences cell cycle progression by limiting fatty acid synthesis required for proliferation. Elucidation of the mechanisms by which lipid metabolism may control cell cycle in myeloid progenitor cells is an important issue for further study. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".